tbuckley/cabot-search huggingface dataset:
CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1–positive regulator for tumor immune evasion
Authors: Shengnan Wang, Radhika Iyer, Xiaohua Han, Juncheng Wei, Na Li, Yang Cheng, Yuanzhang Zhou, Qiong Gao, Lingqiang Zhang, Ming Yan, Zhaolin Sun, Deyu Fang
Journal: Journal of Clinical Investigation (2023)

Regulation of tumoral PD-L1 expression is critical to advancing our understanding of tumor immune evasion and the improvement of existing antitumor immunotherapies. Herein, we describe a CRISPR-based screening platform and identified ATXN3 as a positive regulator for PD-L1 transcription. TCGA database analysis revealed a positive correlation between ATXN3 and CD274 in more than 80% of human cancers. ATXN3-induced Pd-l1 transcription was promoted by tumor microenvironmental factors, including the inflammatory cytokine IFN-γ and hypoxia, through protection of their downstream transcription factors IRF1, STAT3, and HIF-2α. Moreover, ATXN3 functioned as a deubiquitinase of the AP-1 transcription factor JunB, indicating that ATNX3 promotes PD-L1 expression through multiple pathways. Targeted deletion of ATXN3 in cancer cells largely abolished IFN-γ- and hypoxia-induced PD-L1 expression and consequently enhanced antitumor immunity in mice, and these effects were partially reversed by PD-L1 reconstitution. Furthermore, tumoral ATXN3 suppression improved the preclinical efficacy of checkpoint blockade antitumor immunotherapy. Importantly, ATXN3 expression was increased in human lung adenocarcinoma and melanoma, and its levels were positively correlated with PD-L1 as well as its transcription factors IRF1 and HIF-2α. Collectively, our study identifies what we believe to be a previously unknown deubiquitinase, ATXN3, as a positive regulator for PD-L1 transcription and provides a rationale for targeting ATXN3 to sensitize checkpoint blockade antitumor immunotherapy.
A case of fatal monkeypox infection: necropsy and molecular findings, with some considerations related to clinical management
Authors: María Paniagua-García, Carlos S. Casimiro-Soriguer, David Chinchón, Mª Dolores Navarro-Amuedo, Rafael Luque-Márquez, Enrique de Álava, Jose A. Lepe, José M. Cisneros
Journal: Clinical Microbiology and Infection (2023)
Advances in understanding the mechanism of action of adult vaccines
Authors: Anthony L. Cunningham, Kerrie J. Sandgren, Naomi R. Truong
Journal: Journal of Clinical Investigation (2023)

The occurrence of herpes zoster (HZ) correlates with declining memory T cells that had responded to earlier infection with varicella-zoster virus (VZV). There are especially lower T cell responses to the single immunodominant VZV protein glycoprotein E (gE) in people over 50 years of age, although antibody responses to VZV persist. Therefore, a live attenuated zoster vaccine (ZVL) aimed at restoring T cell responses was developed. Surprisingly, a recombinant zoster vaccine (RZV) consisting of gE combined with the AS01B adjuvant system proved superior in efficacy and durability. In this issue of the JCI, Laing, Ford, and colleagues showed that both vaccines stimulated preimmunization naive CD4+ T cells, not just memory CD4+ T cells, to gE, and recruited these naive responses into the overall memory response. However, compared with ZVL, RZV stimulated this response to a much greater degree. These results will help guide development of more effective and durable vaccines for older individuals.
2023 Atrial Fibrillation Guideline-at-a-Glance
Authors: Barbara S. Wiggins, Nicole M. Bhave, Niti R. Aggarwal, Katie Bates, Biykem Bozkurt, John P. Erwin, Dharam J. Kumbhani, Gurusher S. Panjrath, David E. Winter, Megan Coylewright, Morgane Cibotti-Sun, Mykela M. Moore
Journal: Journal of the American College of Cardiology (2023)
Clinical application of bladder MRI and the Vesical Imaging-Reporting And Data System
Authors: Valeria Panebianco, Alberto Briganti, Thierry N. Boellaard, James Catto, Eva Comperat, Jason Efstathiou, Antoine G. van der Heijden, Gianluca Giannarini, Rossano Girometti, Laura Mertens, Mitsuru Takeuchi, Valdair F. Muglia, Yoshifumi Narumi, Giacomo Novara, Martina Pecoraro, Morgan Roupret, Francesco Sanguedolce, Daniele Santini, Shahrokh F. Shariat, Giuseppe Simone, Hebert A. Vargas, Sungmin Woo, Jelle Barentsz, J. Alfred Witjes
Journal: Nature Reviews Urology (2023)
Pangenome analysis reveals genomic variations associated with domestication traits in broomcorn millet
Authors: Jinfeng Chen, Yang Liu, Minxuan Liu, Wenlei Guo, Yongqiang Wang, Qiang He, Weiyao Chen, Yi Liao, Wei Zhang, Yuanzhu Gao, Kongjun Dong, Ruiyu Ren, Tianyu Yang, Liyuan Zhang, Mingyu Qi, Zhiguang Li, Min Zhao, Haigang Wang, Junjie Wang, Zhijun Qiao, Haiquan Li, Yanmiao Jiang, Guoqing Liu, Xiaoqiang Song, Yarui Deng, Hai Li, Feng Yan, Yang Dong, Qingquan Li, Tao Li, Wenyao Yang, Jianghui Cui, Hongru Wang, Yongfeng Zhou, Xiaoming Zhang, Guanqing Jia, Ping Lu, Hui Zhi, Sha Tang, Xianmin Diao
Journal: Nature Genetics (2023)

Abstract Broomcorn millet ( Panicum miliaceum L.) is an orphan crop with the potential to improve cereal production and quality, and ensure food security. Here we present the genetic variations, population structure and diversity of a diverse worldwide collection of 516 broomcorn millet genomes. Population analysis indicated that the domesticated broomcorn millet originated from its wild progenitor in China. We then constructed a graph-based pangenome of broomcorn millet based on long-read de novo genome assemblies of 32 representative accessions. Our analysis revealed that the structural variations were highly associated with transposable elements, which influenced gene expression when located in the coding or regulatory regions. We also identified 139 loci associated with 31 key domestication and agronomic traits, including candidate genes and superior haplotypes, such as LG1 , for panicle architecture. Thus, the study’s findings provide foundational resources for developing genomics-assisted breeding programs in broomcorn millet.
FDA Investigating CAR-Related T-cell Malignancies
Journal: Cancer Discovery (2023)

The FDA is investigating reports that BCMA- and CD19-directed autologous chimeric antigen receptor T-cell immunotherapies, which are used to treat a variety of blood cancers, may be causing secondary malignancies. However, the agency and hematologists say the potential benefits of the agents, which have saved thousands of lives, outweigh this risk.
East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic insights into peptic ulcer disease
Authors: Yunye He, Masaru Koido, Yoichi Sutoh, Mingyang Shi, Yayoi Otsuka-Yamasaki, Hans Markus Munter, Yoishinori Murakami, Takayuki Morisaki, Akiko Nagai, Yoshinori Murakami, Chizu Tanikawa, Tsuyoshi Hachiya, Koichi Matsuda, Atsushi Shimizu, Yoichiro Kamatani
Journal: Nature Genetics (2023)

Abstract Peptic ulcer disease (PUD) refers to acid-induced injury of the digestive tract, occurring mainly in the stomach (gastric ulcer (GU)) or duodenum (duodenal ulcer (DU)). In the present study, we conducted a large-scale, cross-ancestry meta-analysis of PUD combining genome-wide association studies with Japanese and European studies (52,032 cases and 905,344 controls), and discovered 25 new loci highly concordant across ancestries. An examination of GU and DU genetic architecture demonstrated that GUs shared the same risk loci as DUs, although with smaller genetic effect sizes and higher polygenicity than DUs, indicating higher heterogeneity of GUs. Helicobacter pylori (HP)-stratified analysis found an HP-related host genetic locus. Integrative analyses using bulk and single-cell transcriptome profiles highlighted the genetic factors of PUD being enriched in the highly expressed genes in stomach tissues, especially in somatostatin-producing D cells. Our results provide genetic evidence that gastrointestinal cell differentiations and hormone regulations are critical in PUD etiology.
Interactions between insulin resistance, epigenetics, and donor sex in gene expression regulation of iPSC-derived myoblasts
Authors: Nida Haider, C. Ronald Kahn
Journal: Journal of Clinical Investigation (2023)

About 25% of people within the general population are insulin resistant, increasing the risk for type 2 diabetes (T2D) and metabolic disease. Transcriptomic analysis of iPS cells differentiated into myoblasts (iMyos) from insulin resistant (I-Res) versus insulin sensitive (I-Sen) non-diabetic individuals reveals 306 genes increased and 271 genes decreased in expression in iMyos from insulin resistant donors with differences of 2-folds or more. Over 30 of the genes changed in I-Res iMyos are associated with T2D by SNP polymorphisms and functionally linked to insulin action and control of metabolism. Interestingly, we also identified >1500 differences in gene expression that were dependent on sex of the cell donor, some of which modified the insulin resistance effects. Many of these sex-differences were associated with increased DNA methylation in cells from females and reversed by 5-azacytidine. By contrast, the insulin sensitivity differences were not reversed and thus appear to reflect genetic or methylation-independent epigenetic effects.
John Launer: Israel and Gaza—recognising shared human values
Authors: John Launer
Journal: BMJ (2023)

All Muslim and Jewish doctors, and many of other faiths or none, will have felt tormented by the recent horrific events in Israel and Gaza.I share with many colleagues not only a sense of despair at the inhumanity of these events but also one of helplessness, in the face of the unfathomably destructive forces underlying them.Anyone with connections to the region will have been especially affected.I have relatives on one side of the border between
Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation
Authors: Han Zhou, Lei Wang, Zhiwen Lin, Chenwei Jiang, Xingte Chen, Kai Wang, Libin Liu, Lingdong Shao, Jianji Pan, Jinluan Li, Da Zhang, Junxin Wu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Preoperative radiation therapy (preRT) is a fundamental aspect of neoadjuvant treatment for rectal cancer (RC), but the response to this treatment remains unsatisfactory. The combination of radiation therapy (RT) and immunotherapy (iRT) presents a promising approach to cancer treatment, though the underlying mechanisms are not yet fully understood. The gut microbiota may influence the response to RT and immunotherapy. Therefore, we aimed to identify the metabolism of gut microbiota to reverse radioresistance and enhance the efficacy of iRT. Methods Fecal and serum samples were prospectively collected from patients with locally advanced rectal cancer (LARC) who had undergone pre-RT treatment. Candidate gut microbiome-derived metabolites linked with radiosensitization were screened using 16s rRNA gene sequencing and ultrahigh-performance liquid chromatography-mass coupled with mass spectrometry. In vitro and in vivo studies were conducted to assess the radiosensitizing effects of the metabolites including the syngeneic CT26 tumor model and HCT116 xenograft tumor model, transcriptomics and immunofluorescence. The CT26 abscopal effect modeling was employed to evaluate the combined effects of metabolites on iRT. Results We initially discovered the gut microbiota-associated metabolite, methylglyoxal (MG), which accurately predicts the response to preRT (Area Under Curve (AUC) value of 0.856) among patients with LARC. Subsequently, we observed that MG amplifies the RT response in RC by stimulating intracellular reactive oxygen species (ROS) and reducing hypoxia in the tumor in vitro and in vivo. Additionally, our study demonstrated that MG amplifies the RT-induced activation of the cyclic guanosine monophosphate AMP synthase-stimulator of interferon genes pathway by elevating DNA double-strand breaks. Moreover, it facilitates immunogenic cell death generated by ROS-mediated endoplasmic reticulum stress, consequently leading to an increase in CD8 + T and natural killer cells infiltrated in the tumor immune microenvironment. Lastly, we discovered that the combination of anti-programmed cell death protein 1 (anti-PD1) therapy produced long-lasting complete responses in all irradiated tumor sites and half of the non-irradiated ones. Conclusions Our research indicates that MG shows promise as a radiosensitizer and immunomodulator for RC. Furthermore, we propose that combining MG with iRT has great potential for clinical practice.
Efficient elimination of MELAS-associated m.3243G mutant mitochondrial DNA by an engineered mitoARCUS nuclease
Authors: Wendy K. Shoop, Janel Lape, Megan Trum, Alea Powell, Emma Sevigny, Adam Mischler, Sandra R. Bacman, Flavia Fontanesi, Jeff Smith, Derek Jantz, Cassandra L. Gorsuch, Carlos T. Moraes
Journal: Nature Metabolism (2023)

Abstract Nuclease-mediated editing of heteroplasmic mitochondrial DNA (mtDNA) seeks to preferentially cleave and eliminate mutant mtDNA, leaving wild-type genomes to repopulate the cell and shift mtDNA heteroplasmy. Various technologies are available, but many suffer from limitations based on size and/or specificity. The use of ARCUS nucleases, derived from naturally occurring I- Cre I, avoids these pitfalls due to their small size, single-component protein structure and high specificity resulting from a robust protein-engineering process. Here we describe the development of a mitochondrial-targeted ARCUS (mitoARCUS) nuclease designed to target one of the most common pathogenic mtDNA mutations, m.3243A&gt;G. mitoARCUS robustly eliminated mutant mtDNA without cutting wild-type mtDNA, allowing for shifts in heteroplasmy and concomitant improvements in mitochondrial protein steady-state levels and respiration. In vivo efficacy was demonstrated using a m.3243A&gt;G xenograft mouse model with mitoARCUS delivered systemically by adeno-associated virus. Together, these data support the development of mitoARCUS as an in vivo gene-editing therapeutic for m.3243A&gt;G-associated diseases.
Decoding motor plans using a closed-loop ultrasonic brain–machine interface
Authors: Whitney S. Griggs, Sumner L. Norman, Thomas Deffieux, Florian Segura, Bruno-Félix Osmanski, Geeling Chau, Vasileios Christopoulos, Charles Liu, Mickael Tanter, Mikhail G. Shapiro, Richard A. Andersen
Journal: Nature Neuroscience (2023)

Brain-machine interfaces (BMIs) enable people living with chronic paralysis to control computers, robots and more with nothing but thought. Existing BMIs have trade-offs across invasiveness, performance, spatial coverage and spatiotemporal resolution. Functional ultrasound (fUS) neuroimaging is an emerging technology that balances these attributes and may complement existing BMI recording technologies. In this study, we use fUS to demonstrate a successful implementation of a closed-loop ultrasonic BMI. We streamed fUS data from the posterior parietal cortex of two rhesus macaque monkeys while they performed eye and hand movements. After training, the monkeys controlled up to eight movement directions using the BMI. We also developed a method for pretraining the BMI using data from previous sessions. This enabled immediate control on subsequent days, even those that occurred months apart, without requiring extensive recalibration. These findings establish the feasibility of ultrasonic BMIs, paving the way for a new class of less-invasive (epidural) interfaces that generalize across extended time periods and promise to restore function to people with neurological impairments.
Evaluation of tissue- and plasma-derived tumor mutational burden (TMB) and genomic alterations of interest in CheckMate 848, a study of nivolumab combined with ipilimumab and nivolumab alone in patients with advanced or metastatic solid tumors with high TMB
Authors: Jie He, Natallia Kalinava, Parul Doshi, Dean C Pavlick, Lee A Albacker, Ericka M Ebot, Hanna Tukachinsky, James Pratt, Gina Fusaro, Geoffrey R Oxnard, George Green, David Fabrizio, Jonathan Baden
Journal: Journal for ImmunoTherapy of Cancer (2023)

An accumulation of somatic mutations in tumors leads to increased neoantigen levels and antitumor immune response. Tumor mutational burden (TMB) reflects the rate of somatic mutations in the tumor genome, as determined from tumor tissue (tTMB) or blood (bTMB). While high tTMB is a biomarker of immune checkpoint inhibitor (ICI) treatment efficacy, few studies have explored the clinical utility of bTMB, a less invasive alternative for TMB assessment. Establishing the correlation between tTMB and bTMB would provide insight into whether bTMB is a potential substitute for tTMB. We explored the tumor genomes of patients enrolled in CheckMate 848 with measurable TMB. The correlation between tTMB and bTMB, and the factors affecting it, were evaluated. In the phase 2 CheckMate 848 (NCT03668119) study, immuno-oncology-naïve patients with advanced, metastatic, or unresectable solid tumors and tTMB-high or bTMB-high (≥10 mut/Mb) were prospectively randomized 2:1 to receive nivolumab plus ipilimumab or nivolumab monotherapy. Tissue and plasma DNA sequencing was performed using the Foundation Medicine FoundationOne CDx and bTMB Clinical Trial Assays, respectively. tTMB was quantified from coding variants, insertions, and deletions, and bTMB from somatic base substitutions. Correlations between tTMB and bTMB were determined across samples and with respect to maximum somatic allele frequency (MSAF). Assay agreement and variant composition were also evaluated. A total of 1,438 and 1,720 unique tissue and blood samples, respectively, were obtained from 1,954 patients and included >100 screened disease ontologies, with 1,017 unique pairs of tTMB and bTMB measurements available for assessment. Median tTMB and bTMB were 3.8 and 3.5 mut/Mb, respectively. A significant correlation between tTMB and bTMB (r=0.48, p<0.0001) was observed across all sample pairs, which increased to r=0.54 (p<0.0001) for samples with MSAF≥1%. Assay concordance was highest for samples with MSAF≥10% across multiple disease ontologies and observed for both responders and non-responders to ICI therapy. The variants contributing to tTMB and bTMB were similar. We observed that tTMB and bTMB had a statistically significant correlation, particularly for samples with high MSAF, and that this correlation applied across disease ontologies. Further investigation into the clinical utility of bTMB is warranted.
BCG vaccination stimulates integrated organ immunity by feedback of the adaptive immune response to imprint prolonged innate antiviral resistance
Authors: Audrey Lee, Katharine Floyd, Shengyang Wu, Zhuoqing Fang, Tze Kai Tan, Heather M. Froggatt, John M. Powers, Sarah R. Leist, Kendra L. Gully, Miranda L. Hubbard, Chunfeng Li, Harold Hui, David Scoville, Alistaire D. Ruggiero, Yan Liang, Anna Pavenko, Victor Lujan, Ralph S. Baric, Garry P. Nolan, Prabhu S. Arunachalam, Mehul S. Suthar, Bali Pulendran
Journal: Nature Immunology (2023)
A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains
Authors: Andras Sziraki, Ziyu Lu, Jasper Lee, Gabor Banyai, Sonya Anderson, Abdulraouf Abdulraouf, Eli Metzner, Andrew Liao, Jason Banfelder, Alexander Epstein, Chloe Schaefer, Zihan Xu, Zehao Zhang, Li Gan, Peter T. Nelson, Wei Zhou, Junyue Cao
Journal: Nature Genetics (2023)

Abstract Conventional methods fall short in unraveling the dynamics of rare cell types related to aging and diseases. Here we introduce EasySci, an advanced single-cell combinatorial indexing strategy for exploring age-dependent cellular dynamics in the mammalian brain. Profiling approximately 1.5 million single-cell transcriptomes and 400,000 chromatin accessibility profiles across diverse mouse brains, we identified over 300 cell subtypes, uncovering their molecular characteristics and spatial locations. This comprehensive view elucidates rare cell types expanded or depleted upon aging. We also investigated cell-type-specific responses to genetic alterations linked to Alzheimer’s disease, identifying associated rare cell types. Additionally, by profiling 118,240 human brain single-cell transcriptomes, we discerned cell- and region-specific transcriptomic changes tied to Alzheimer’s pathogenesis. In conclusion, this research offers a valuable resource for probing cell-type-specific dynamics in both normal and pathological aging.
The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells
Authors: Gene Ching Chiek Koh, Soraya Boushaki, Salome Jingchen Zhao, Andrew Marcel Pregnall, Firas Sadiyah, Cherif Badja, Yasin Memari, Ilias Georgakopoulos-Soares, Serena Nik-Zainal
Journal: Nature Genetics (2023)

Abstract The chemotherapeutic agent CX-5461, or pidnarulex, has been fast-tracked by the United States Food and Drug Administration for early-stage clinical studies of BRCA1- , BRCA2- and PALB2 -mutated cancers. It is under investigation in phase I and II trials. Here, we find that, although CX-5461 exhibits synthetic lethality in BRCA1-/BRCA2 -deficient cells, it also causes extensive, nonselective, collateral mutagenesis in all three cell lines tested, to magnitudes that exceed known environmental carcinogens.
Isoform-level transcriptome-wide association uncovers genetic risk mechanisms for neuropsychiatric disorders in the human brain
Authors: Arjun Bhattacharya, Daniel D. Vo, Connor Jops, Minsoo Kim, Cindy Wen, Jonatan L. Hervoso, Bogdan Pasaniuc, Michael J. Gandal
Journal: Nature Genetics (2023)

Methods integrating genetics with transcriptomic reference panels prioritize risk genes and mechanisms at only a fraction of trait-associated genetic loci, due in part to an overreliance on total gene expression as a molecular outcome measure. This challenge is particularly relevant for the brain, in which extensive splicing generates multiple distinct transcript-isoforms per gene. Due to complex correlation structures, isoform-level modeling from cis-window variants requires methodological innovation. Here we introduce isoTWAS, a multivariate, stepwise framework integrating genetics, isoform-level expression and phenotypic associations. Compared to gene-level methods, isoTWAS improves both isoform and gene expression prediction, yielding more testable genes, and increased power for discovery of trait associations within genome-wide association study loci across 15 neuropsychiatric traits. We illustrate multiple isoTWAS associations undetectable at the gene-level, prioritizing isoforms of AKT3, CUL3 and HSPD1 in schizophrenia and PCLO with multiple disorders. Results highlight the importance of incorporating isoform-level resolution within integrative approaches to increase discovery of trait associations, especially for brain-relevant traits.
Personal transcriptome variation is poorly explained by current genomic deep learning models
Authors: Connie Huang, Richard W. Shuai, Parth Baokar, Ryan Chung, Ruchir Rastogi, Pooja Kathail, Nilah M. Ioannidis
Journal: Nature Genetics (2023)

Genomic deep learning models can predict genome-wide epigenetic features and gene expression levels directly from DNA sequence. While current models perform well at predicting gene expression levels across genes in different cell types from the reference genome, their ability to explain expression variation between individuals due to cis-regulatory genetic variants remains largely unexplored. Here, we evaluate four state-of-the-art models on paired personal genome and transcriptome data and find limited performance when explaining variation in expression across individuals. In addition, models often fail to predict the correct direction of effect of cis-regulatory genetic variation on expression.